US11174218B2 - Glycine particles - Google Patents

Glycine particles Download PDF

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US11174218B2
US11174218B2 US16/079,340 US201716079340A US11174218B2 US 11174218 B2 US11174218 B2 US 11174218B2 US 201716079340 A US201716079340 A US 201716079340A US 11174218 B2 US11174218 B2 US 11174218B2
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glycine
particle size
granules
storage
powder
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US20190047942A1 (en
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Harald BENK
Gudrun BIRK
Melina DECKER
Dieter Lubda
Guenter Moddelmog
Harald MUESSIG
Tanino Scaramuzza
Michael Schleehahn
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Merck Patent GmbH
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/22—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by pressing in moulds or between rollers

Definitions

  • the present invention relates to compacted glycine granules whose particle size is above 0.7 mm, and to a process for the preparation and use of granules of this type.
  • Glycine (aminoacetic acid) is an a-amino acid which is not chiral and is thus also not optically active. Gylcine is typically obtained as a colourless, crystalline solid which is readily water-soluble. The melting point is about 234° C. (decomposition).
  • Glycine fulfils important functions in many metabolic processes, in particular as a constituent of many proteins, such as, for example, the connective tissue protein collagen, as a component for the synthesis of haem or in the function as neurotransmitter in the central nervous system.
  • Glycine is employed, for example, in food supplements or in biochemical buffer systems. Glycine is frequently also used as a component in nutrient formulations for use in intensive medicine and in biotechnological nutrient media. Glycine is frequently required in large amounts for these areas of application.
  • glycine For industrial further processing, glycine must be in free-flowing form in order that it can easily be removed from transport containers and can be treated without problems in the machines for the preparation of the desired formulations.
  • severe lump formation or even complete caking (monoblock formation) of the material repeatedly occurs in the containers—irrespective of the size and type—that it can no longer be removed from the containers in free-flowing form.
  • This causes the users considerable problems in the course of production, since the caked material must first be mechanically comminuted again (which is no longer possible in practice in the case of some types of container). This caking in some cases takes place after storage for only a few weeks.
  • the object of the present invention was therefore to find a way of providing glycine powder in a storage-stable and flowable form.
  • the present invention therefore relates to glycine granules where at least 75% (w/w) of the glycine granules have a particle size of at least 0.7 mm. In a preferred embodiment, 85%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 0.7 mm.
  • 80%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 0.8 mm.
  • 80%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 1 mm.
  • the glycine granules have a bulk density of less than or equal to 0.9 g/ml, preferably between 0.5 and 0.8 g/ml.
  • the glycine granules have a tapped density of less than or equal to 1 g/ml, preferably between 0.6 and 0.9 g/ml.
  • the glycine granules have a drying loss of not greater than 0.3%, preferably not greater than 0.2%, particularly preferably not greater than 0.1%.
  • the glycine granules are flowable after storage for 3, preferably 6, particularly preferably 12 months in a closed container at room temperature.
  • the atmospheric humidity of the environment during storage is preferably between 20 and 30% RH.
  • the present invention also relates to glycine granules where at least 75% (w/w) of the glycine granules have a particle size of at least 0.7 mm, which can be prepared by compaction.
  • 85%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 0.7 mm.
  • 80%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 0.8 mm.
  • 80%, particularly preferably 90%, in particular 95%, of the granules have a particle size of at least 1 mm.
  • the percentage data here in each case relate to the weight of the granules (w/w).
  • the preparation is carried out by
  • the glycine provided is typically in powder form.
  • the particle size of at least 75% (w/w) of the powder particles is below 0.7 mm.
  • the pressing force of the roller compactor in step b) is between 1 and 50 KN/cm of roller width.
  • the preparation is carried out by
  • the recycling in step c) is carried out by crushing the compacts and classification by particle size, where at least some of the glycine particles that have a particle size smaller than 0.7 mm are recycled to the glycine provided in step a).
  • the present invention also relates to a process for the preparation of glycine granules where at least 75% (w/w) of the glycine granules have a particle size of at least 0.7 mm, by
  • the compaction is carried out in a roller compactor.
  • the preparation is carried out by
  • the pressing force of the roller compactor in step b) is between 1 and 50 KN/cm of roller width.
  • the recycling in step c) is carried out by crushing the compacts and classification by particle size, where at least some of the glycine particles that have a particle size smaller than 0.7 mm are recycled to the glycine provided in step a).
  • the invention accordingly also relates to glycine granules which can be prepared by the process according to the invention.
  • the present invention also relates to the use of glycine granules where at least 75% (w/w) of the glycine granules have a particle size of at least 0.7 mm, in particular the glycine granules compacted in accordance with the invention, for the preparation of nutrient media for medical applications or in biotechnology.
  • FIG. 1 shows diagrammatically a possible arrangement for carrying out the process according to the invention.
  • compaction or compacting of solids means the preparation of particles of a solid which are larger in relation to the starting material by compressing the starting material under pressure.
  • the compaction is carried out without addition of water or other solvents. It is dry compaction.
  • the compaction can be carried out, for example, in roller compactors, eccentric tablet presses or rotary presses. In accordance with the invention, the compaction is preferably carried out in roller compactors.
  • Roller compactors are also called roller presses or roll presses. These are pressing machines having two preferably counterrotating rollers.
  • the rollers have a certain separation from one another and thus form a gap. The material to be compacted is forced through this gap. Gap width and length of the rollers or the gap formed vary depending on the model.
  • the rollers can be arranged vertically, horizontally or tilted.
  • the rollers can have a profile or preferably have a smooth or grooved surface.
  • roller compactors which are suitable in accordance with the invention are available, for example, from Alexanderwerk, Sahut Conreur, Hosokawa or Fitzpatrick Company.
  • classification denotes the separation of a disperse solid mixture into fractions by particle size.
  • Classification is preferably carried out by means of sieving.
  • Alternative classification methods are classification or vibration.
  • the result of a classification are at least two fractions which differ in that the minimum limit of the particle size of one fraction is at the same time the maximum limit of the other fraction. Solids particles which lie precisely in between are called limit-size particles. This is, however, an idealised consideration of the separation process. In practice, in particular in the case of powders classified by sieving, transition regions of various size exist between the classes.
  • Sieving is a mechanical separation process for size separation (classification) of bulk materials or disperse solids mixtures.
  • the material to be separated is placed on a sieve, which is, for example, set in rotation or shaken.
  • the driving force for the sieving is generally gravity.
  • the material to be separated is moved by shaking, vibration and/or tumbling.
  • Sieving is determined by the passage probability of a particle for a given mesh width. In industry, this is carried out, for example, using a gyratory sieve, a tumble sieving machine or vibration sieving machine.
  • the sieves are often arranged in several sieve layers one above the other.
  • the size of a particle is determined by sieving.
  • a set with sieves becoming finer and finer in the downward direction is placed one on the other here.
  • the sample to be analysed is introduced into the uppermost sieve and the sieve set is subsequently clamped into a sieving machine.
  • the machine then shakes or vibrates the sieve set with a certain amplitude for a certain time. If, for example, a particle does not pass through a sieve having a mesh width of 0.7 mm, the particle thus has a particle size of greater than 0.7 mm.
  • the result of particle size analysis by means of sieving is the particle size distribution, i.e. a frequency distribution.
  • the usual statistical parameters such as mean, median, percentile values, scatter or skew of distribution, can be calculated therefrom and the sample thus characterised with respect to its particle size.
  • a particle size distribution can be narrow or broad, depending on the magnitude of the differences in particle size in a sample.
  • Powders are piles of solid particles.
  • the individual particles differ through size, shape, mass and surface area.
  • the cohesion is ensured by cohesion forces.
  • Powders can be crystals, amorphous substances, aggregates or agglomerates.
  • glycine powder is used for mixtures of glycine particles of which less than 75% (w/w) have a particle size of at least 0.7 mm.
  • Granules consist of grains or particles.
  • the granules according to the invention consists of grains or particles of which at least 75% (w/w) have a particle size of at least 0.7 mm.
  • the granules according to the invention preferably consist of particles or grains which are an agglomerate of powder particles. This means that the granule particles have formed by compaction of powder particles.
  • Granule particles typically have an asymmetrical shape.
  • a powder is referred to as caked if its particles are no longer freely mobile against one another and which is therefore no longer flowable or free-flowing. This feature is typically determined visually. Whereas slightly caked powders are possibly still mobile against one another as relatively large lumps, heavily caked powders usually form a type of monolithic block. Lumps or block must, if appropriate, be mechanically destroyed in order to obtain a free-flowing powder again.
  • a flowable or free-flowing powder can, for example, be poured evenly out of a vessel without relatively large lumps.
  • Granules are storage-stable if they do not change their properties significantly over the time of their storage. For example, glycine granules are storage-stable if they remain flowable during the storage time.
  • the properties of the solid glycine can be strongly influenced by changing the particle size.
  • caking can be influenced.
  • glycine in the form of fine particles having a particle size below 0.5 mm, in particular below 0.1 mm frequently tends towards uncontrolled caking, even with exclusion of moisture, this is substantially prevented by compaction of fine particles to give relatively large compact particles having a particle size of above 0.7 mm.
  • the particles are preferably not subjected to any further treatment step. The compaction is carried out without addition of reagents, such as water or other solvents.
  • roller compactors are known to the person skilled in the art and are commercially available. Particularly suitable in accordance with the invention are roller compactors having a separation between the rollers of 0.5 to 3 mm, preferably between 1 and 2 mm. Roller compactors which are particularly suitable in accordance with the invention have rollers having a width between 10 and 50 cm, so that the gap between the two rollers has a length between 10 and 50 cm.
  • the pressing force of the roller compactor is typically between 0.1 and 100 kN/cm of roller width.
  • the rollers are preferably pressed together with a force between 1 and 50 kN.
  • roller compactor The feed of the glycine provided into the roller compactor preferably takes place by means of one or more screws.
  • roller compactors By pressing powders between preferably counterrotating rolls, roller compactors produce larger compacts of the powders.
  • plate-shaped, flake-form and/or lump-form compacts are frequently obtained.
  • the shape and size of the compacts obtained from the roller compactor is typically very irregular and can be influenced by the further processing. Merely transfer or packaging of the compacts will typically lead to partial breakage of the flakes.
  • the compacts obtained directly from the roller compactor are therefore preferably broken up into granules or larger particles in a further process step.
  • This can be carried out, for example, by a roller crusher with subsequent sieving through a vibrating sieve or friction sieve, by a rotor homogenisation mill or an oscillating mill (oscillating vibration mill).
  • Granule particles comprising pressed powder are thus obtained from the irregular, lump-form compacts.
  • the size of the particles can be adjusted through the mesh width of the sieve. In this way, it is also possible to influence the upper limit of the particle size.
  • Granules whose particle size is not greater than 5 mm are preferably produced.
  • the compacts or compacts broken up to give compacted particles are subsequently preferably classified.
  • This enables a more homogeneous material with respect to the particle size to be obtained and in addition at least some of the fines content is preferably separated off.
  • the fines content denotes particles which have a particle size below the desired minimum particle size of, for example, 0.7 mm, 0.8 mm or 1 mm.
  • granules having a low or high fines content can be obtained. In the grand case of granules having a low fines content, it is typically not necessary to separate this off. However, if this is desired or necessary in order to meet the product specification with respect to the particle size contents, classification can be carried out. In order to avoid loss of material and to re-use the fines content, the latter can be separated off and re-added to the material subjected to compaction.
  • the classification and performance of the recycling make it possible to determine what proportion of the particles is recycled. If particles having a particle size of below, for example, 0.7 mm are separated off during the classification, these can all be recycled. However, further sub-groups can also be produced, more precisely the particles having a particle size of, for example, below 0.7 mm can be separated off from the product, but not recycled in full, but instead, for example, only particles below 0.5 mm or below 0.2 mm.
  • the classification can be carried out in such a way that only particles having a particle size of, for example, 0.5 mm or 0.2 mm are separated off and recycled, so the product still has a content of particles having a particle size of 0.5 mm or 0.2 mm up to, for example, 0.7 mm—so long as this proportion does not exceed the maximum fines content defined for the corresponding product.
  • all or some of the fines content is removed from the product by classification and preferably continuously mixed again in its entirety with the material provided in step a) and thus fed to the compaction step again.
  • This recycling reduces the fines content in the desired compacted product without the need to accept a loss of material.
  • granules of glycine have a significantly lower tendency to cake if they consist of particles of which at least 75% (w/w) have a particle size of at least 0.7 mm.
  • the granules have preferably been produced by means of compaction. They particularly preferably have a fines content of less than 20%, particularly preferably less than 10% (w/w).
  • FIG. 1 shows diagrammatically a possible arrangement for carrying out the process according to the invention.
  • the roller compactor is depicted with rollers R 1 and R 2 .
  • the glycine powder P 1 is fed to the roller compactor from a reservoir by means of gravity.
  • a transport screw not depicted in FIG. 1 can also be used for this purpose.
  • the compacted product released from the roller compactor is broken up and classified by means of a grinding and sieving device, depicted as sieve S.
  • the desired product fraction is removed for further use and optionally packaging and the fines content P 2 , which has a particle size below, for example, 0.7 mm, is fed continuously back to the pulverulent glycine, which is introduced into the roller compactor.
  • the present invention also relates to glycine granules where at least 75% (w/w) of the glycine granules have a particle size of at least 0.7 mm.
  • This glycine is preferably prepared by means of compaction. This glycine is therefore also called compacted glycine granules below. This glycine preferably has a fines content of less than 20%, particularly preferably less than 10% (w/w).
  • the compacted glycine granules have a bulk density of less than or equal to 0.9 g/ml, preferably between 0.5 and 0.8 g/ml.
  • the compacted glycine granules have a tapped density of less than or equal to 1 g/ml, preferably between 0.6 and 0.9 g/ml.
  • the compacted glycine granules have a drying loss of not greater than 0.3%, preferably not greater than 0.2%, particularly preferably not greater than 0.1%.
  • the compacted glycine granules have a Hausner factor of less than or equal to 1.18 and a compressibility index of less than or equal to 15%.
  • the storage stability of the compacted glycine granules is significantly better than that of the pulverulent starting material. While the pulverulent starting material cakes after only a few weeks and is thus no longer flowable, the compacted glycine granules cake significantly less and/or significantly later. For example, the compacted glycine granules do not cake at all on open storage for 7 weeks at 25° C. and 60% RH, whereas the pulverulent material cakes after only one week. Further comparisons under different storage conditions are given in the examples.
  • a container is any type of packaging which is suitable for the storage of powders or granules and can be sealed. Containers of this type are known to the person skilled in the art. Preferred containers are screw-lid containers made of glass or plastic, such as, for example, made from PE, PE sacks, big bags or plastic drums.
  • compacted glycine granules exhibit a similar dissolution behaviour to pulverulent glycine. This means that compacted glycine granules can be brought into solution just as quickly as pulverulent, uncompacted glycine under the same conditions.
  • the present invention also relates to the use of the compacted glycine granules for the preparation of nutrient media for medical applications or in biotechnology.
  • nutrient media of this type are, in particular, injection solutions, infusion solutions and cell culture media.
  • Nutrient media of this type are typically in the form of a solids mixture or aqueous solution.
  • the compacted glycine granules can be added to the media in the form of a solid or can be dissolved in water or another solvent and then added to the nutrient media.
  • Processes for the preparation of nutrient media are known to the person skilled in the art.
  • the components of the nutrient medium are preferably mixed and ground in solid form. They are subsequently dissolved by addition of water or an aqueous buffer. Whereas hygroscopic or unstable components may have to be stored and brought into solution separately, the compacted glycine granules can readily be processed with the other stable components.
  • the present invention also relates to a process for increasing the storage stability of glycine powder, in particular for retaining the flowability of glycine.
  • glycine powder is compacted to give glycine granules, where at least 75% (w/w) of the glycine granules obtained have a particle size of at least 0.7 mm.
  • the preferred embodiments of the preparation process of compacted glycine granules mentioned above apply here.
  • the process can be carried out at room temperature.
  • the glycine granules obtained by means of the process have a significantly higher storage stability than the glycine powder employed as starting material. In particular, the flowability is maintained for longer compared with glycine powder under identical storage conditions.
  • the processes according to the invention are simple and effective to carry out. Without a chemical change to the glycine, the properties of the glycine can be modified purely by mechanical actions, such as pressing and optionally sieving. In particular, a significant increase in the storage stability takes place, since the material according to the invention cakes significantly more slowly and remains flowable for longer.
  • Procedure place 50 ml of DI water in the beaker and switch on the stirrer. Place the thermometer in the DI water, add the substance and measure the time (stopwatch) until the substance has visually dissolved without a residue.
  • Comparisons 1 and 2 and Examples E and F in each case 160 g+/ ⁇ 5 g of substance are stored at 25° C./60% RH and 40° C./75% RH both open (in a glass dish) and also closed (in a screw-lid glass container)—the caking is assessed after a storage time of 1, 2 and 7 weeks.
  • Examples A, B, C and D in each case 120 g+/ ⁇ 5 g of substance are stored at 40° C./75% RH both open (in a glass dish) and also closed (in a screw-lid glass container)—the caking is assessed after a storage time of 2 and 7 weeks.
  • REVOLUTION powder analyzer (Mercury Scientific Inc, Newton, USA); rotation rate 0.3 rpm, test method FlowMethod_SP.fam; drum diameter 100 mm; amount of powder 95-100 ml
  • REVOLUTION powder analyzer (Mercury Scientific Inc, Newton, USA); rotation rate 0.3 rpm, test method FlowMethod_SP.fam; drum diameter 100 mm; amount of powder 95-100 ml
  • crystalline pulverulent glycine (Article 100590 glycine cryst. Suitable for use as excipients EMPROVE® exp Ph Eur, BP, JP, USP from Merck KGaA, Darmstadt, Germany) is subjected to dry granulation over roller compactors with subsequent crushing and sieving via an oscillating sieve mill.
  • Examples A to D model RC 100 compactor from powtec Maschinen and Engineering, Remscheid, Germany; roller diameter 100 mm, roller width 30 mm, grooved roller surface, no roller cooling, sieve mesh width 3 mm, undersized particle sieving 1 mm without material recycling; the gap width arises through the roller pressure selected
  • Examples E and F model K200/100 compactor with FC 400 sieve mill from Hosokawa Bepex, Leingart, Germany; roller diameter 200 mm, roller width 100 mm, grooved roller surface, no roller cooling, sieve mesh width 2 mm; undersized particle sieving 1 mm with material recycling; the gap width arises through the roller pressure selected
  • Examples A, B, C and D preparation of a compacted glycine having improved flowability and storage stability (compacted glycine having coarse fractions >2000 ⁇ m prepared under various roller pressures)
  • Example A 0.72 0.82 1.14 12.7 0.02
  • Example B 0.72 0.82 1.13 11.4 0.04
  • Example C 0.72 0.80 1.12 10.5 0.05
  • Example D 0.73 0.82 1.12 10.6 0.04
  • Example E Example E
  • Comparisons 1 and 2 commercially available crystalline glycine 2 batches of a commercially available glycine are employed for comparative purposes (as prior art)
  • comparisons exhibit a very low water content and also comparable bulk and tapped densities, they differ in the level of the Hausner factor and in the compressibility index (in accordance with Ph Eur 6th Edition, Table 2.9.36-2 “Scale of flowability”, comparison 1 should be classified as “good” comparison 2 as “satisfactory”)—in the visual assessment, comparison 2 already exhibits slight caking tendencies compared with comparison 1, but where the agglomerates can be destroyed by slight application of pressure.
  • Example A no storage takes place
  • Example B no storage takes place
  • Example C no storage takes place
  • Example D no storage takes place
  • Example E 0.03 0.05 0.05 0.09
  • Example F 0.03 0.09 0.02 0.09 Comparison 1 0.02 0.07 0.01 0.04 Comparison 2 0.02 0.05 0.04 0.02
  • Example A no storage takes place
  • Example B no storage takes place
  • Example C no storage takes place
  • Example D no storage takes place
  • Example E 0.03 0.06 0.03 0.08
  • Example F 0.03 0.08 0.06 0.10 Comparison 1 0.02 0.01 0.02 0.04 Comparison 2 0.02 0.05 0.03 0.02
  • Example A 0.02 — 0.01 0.02
  • Example B 0.04 — 0.04 ⁇ 0.01
  • Example C 0.05 — ⁇ 0.01 0.01
  • Example D 0.04 — ⁇ 0.01 ⁇ 0.01
  • Example E 0.03 0.06 0.03 0.08
  • Example F 0.03 0.04 0.04 0.07 Comparison 1 0.02 0.01 0.01 0.04 Comparison 2 0.02 0.04 0.03 0.03
  • Example A 0.02 — ⁇ 0.01 ⁇ 0.01
  • Example B 0.04 — 0.04 ⁇ 0.01
  • Example C 0.05 — ⁇ 0.01 0.01
  • Example D 0.04 — 0.02 0.025
  • Example E 0.03 0.01 0.03 0.08
  • Example F 0.03 0.08 0.04 0.09 Comparison 1 0.02 0.03 0.02 0.04 Comparison 2 0.02 0.05 0.02 0.03
  • Example A 358 ⁇ 12 — 335 ⁇ 11 313 ⁇ 5
  • Example B 347 ⁇ 11 — 340 ⁇ 16 309 ⁇ 12
  • Example C 339 ⁇ 6 — 346 ⁇ 18 324 ⁇ 20
  • Example D 348 ⁇ 5 — 332 ⁇ 9 270 ⁇ 10
  • Example A 358 ⁇ 12 — 350 ⁇ 23 297 ⁇ 4
  • Example B 347 ⁇ 11 — 332 ⁇ 12 304 ⁇ 9
  • Example C 339 ⁇ 6 — 326 ⁇ 10 299 ⁇ 6
  • Example D 348 ⁇ 5 — 319 ⁇ 11 290 ⁇ 1
  • Example E 318 ⁇ 20 322 ⁇ 8 343 ⁇ 5 343 ⁇ 14
  • Example F 316 ⁇ 15 316 ⁇ 7 350 ⁇ 15 342 ⁇ 12 Comparison 1 233 ⁇ 51 177 ⁇ 6 215 ⁇ 8 203 ⁇ 4 Comparison 2 127 ⁇ 11 201 ⁇ 17 193 ⁇ 10 215 ⁇ 9
  • Free-flowing the glycine flows freely without input of force—agglomerates are not visually evident.
  • “Lumpy” the glycine exhibits individual relatively large agglomerates (and encrustations (of diameter about 1 cm), but is still free-flowing.
  • “Slightly caked” the glycine is solid; however, it can be converted back into the free-flowing state by slight input of force (gentle poking with a glass rod or spatula, hitting or shaking).
  • Example A free- — free-flowing free-flowing flowing (weak agglomerates)
  • Example B free- — free-flowing free-flowing flowing
  • Example C free- — free-flowing free-flowing flowing
  • Example D free- — free-flowing free-flowing flowing
  • Example E free- free-flowing free-flowing free-flowing flowing
  • Example F free-free-flowing free-flowing free-flowing flowing Comparison 1 free- strongly caked strongly strongly caked flowing caked Comparison 2 lumpy strongly caked strongly strongly caked caked
  • n.m. not measurable since the material has already caked too strongly in order to be removed from the vessel (too many agglomerates are present or the material has to be poked out of the dish/bottle)
  • n.m. not measurable since the material has already caked too strongly in order to be removed from the vessel (too many agglomerates are present or the material has to be poked out of the dish/bottle)

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DE69706988T2 (de) 1996-06-17 2002-04-04 Powderject Research Ltd., Oxford Verfahren zur lieferung von zusammensetzungen aus dichten teilchen zur anwendung in transdermale teilchen abgabe
US6893664B1 (en) 1996-06-17 2005-05-17 Powderject Research Limited Particle delivery techniques
JPH11276553A (ja) 1998-03-26 1999-10-12 Jgc Corp 固形製剤の製造方法およびそのための製造装置
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EP3419606A1 (de) 2019-01-02
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DK3419606T3 (da) 2020-03-16
JP2019507670A (ja) 2019-03-22
KR20180115781A (ko) 2018-10-23
CN108697647B (zh) 2022-04-05
MX2018010049A (es) 2018-11-09
SG11201807106WA (en) 2018-09-27
CN108697647A (zh) 2018-10-23
BR112018016634B1 (pt) 2023-11-21
US20190047942A1 (en) 2019-02-14
ES2781433T3 (es) 2020-09-02
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PH12018501372A1 (en) 2019-02-18
BR112018016634A2 (pt) 2018-12-26

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